ESPE Abstracts (2019) 92 RFC6.6

Genetic Aetiology Predicts Growth Hormone (GH) Treatment Outcomes in Children Born Small-For-Gestational-Age with Persistent Short Stature (SGA-SS). Lessons from a Single-Centre Cohort

Jan Lebl, Ledjona Toni, Lukas Plachy, Petra Kucerova, Lenka Elblova, Zdenek Sumnik, Stanislava Kolouskova, Marta Snajderova, Barbora Obermannova, Stepanka Pruhova

Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

Background: SGA-SS, defined as birth weight and/or birth length below -2SD for gestational age and postnatal statural height below -2.5SD according to age- and sex-specific standards, is a heterogeneous condition reflexing exogenous (maternal, placental) or endogenous (foetal) inadequacies. Within the past two decades, a handful of genetic causes of SGA-SS have been elucidated. However, how each genetic aetiology impacts individual GH treatment outcomes awaits clarification.

Aim: To analyse treatment outcomes in genetically defined subgroups of SGA-SS children originating from a single-centre cohort.

Patients/Methods: A single-centre cohort consists of 445 SGA-SS children (221 females; Turner syndrome was excluded) aged 1.3-27.0 years at this evaluation (median 11.8). Of these, genetic aetiology was thus far elucidated in 60 children (33 females) – 24 carried a pathogenic variant of genes affecting the cartilage (ACAN in two, collagen genes in nine, and SHOX gene in 13), 19 had pathogenic genetic variants perturbing GH-IGF axis and signalling (GHSR [1], HGMA2 [3], OTX2 [1], STAT3 [1], IGFALS [1], IGF1R [2], Silver-Russell syndrome [SRS; 10]), and 17 had miscellaneous single-gene or chromosomal conditions.

We analysed (1) systemic response to GH administration expressed as delta-IGF-1_SDS prior to and while on treatment and (2) target tissue response expressed as delta-height_SDS on treatment.

Results: Whereas the systemic response to GH therapy was equivalent in children with undetermined aetiology of SGA-SS (delta-IGF-1_SDS following the first 3-6 months of GH: +1.50±0.10; mean±SEM) and the subcohorts with cartilage defects (+1.47±0.36) and perturbed GH-IGF axis (+1.42±0.46), the target tissue response clearly differed. The height gain following first two years of prepubertal GH therapy was higher in the subcohort with perturbed GH-IGF axis (delta-height SDS: +1.12±0.09) than in children with cartilage defects (delta-height SDS: +0.84±0.09; P=0.046), whereas children with undetermined aetiology had an intermediate two-year growth response (delta-height SDS: +0.96±0.04).

Conclusions: The best SGA-SS responders to GH therapy are apparently children with perturbed GH-IGF axis and signalling, including SRS children. The treatment response in children with defective growth cartilage (bearing either cartilaginous matrix or chondrocyte regulation defect) was rather modest. The change of IGF-1 following therapy is a poor predictor of growth outcome. Our results open an insight into treatment outcome prediction in SGA-SS, however their reproducibility may be limited due to small counts in individual subcohorts. Thus, analyses in larger cohorts of genetically defined SGA-SS children are warranted.